Alexander Popov1, Guenter Henze2, Tatiana Verzhbitskaya3,4, Julia Roumiantseva5,6, Svetlana Lagoyko5, Olga Khlebnikova3, Olga Streneva3,4, Oleg Bidanov7, Grigory Tsaur3,4, Hiroto Inaba8, Alexander Karachunskiy5,6, Larisa Fechina3,4. 1. Head of Flow Cytometry Laboratory, National Research Center of Pediatric Hematology, Oncology and Immunology, 1, S. Mashela str., 117998, Moscow, Russian Federation. uralcytometry@gmail.com. 2. Klinik für Pädiatrische Onkologie und Hämatologie, Charité CVK, Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. 3. Regional Children Hospital, 32, S. Deryabina Str., 620149, Ekaterinburg, Russian Federation. 4. Research Institute of Medical Cell Technologies, 22A, K. Marks str., 620026, Ekaterinburg, Russian Federation. 5. Head of Flow Cytometry Laboratory, National Research Center of Pediatric Hematology, Oncology and Immunology, 1, S. Mashela str., 117998, Moscow, Russian Federation. 6. Pirogov Russian National Research Medical University, 1, Ostrovitianova str., 117997, Moscow, Russian Federation. 7. Belarussian Research Center for Pediatric Oncology, Hematology and Immunology, 43, Frunzenskaya st., 223053, Borovlyani, Minsk Region, Belarus. 8. St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA.
Abstract
BACKGROUND: Usually, central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is diagnosed by cytomorphology (CM) of cerebrospinal fluid (CSF) on cytospin slides. Multicolor flow cytometry (MFC) provides the opportunity to detect low numbers of leukemia cells undetectable by CM. The present study aimed at evaluating the clinical significance of MFC for the diagnosis of CNS involvement at initial manifestation of childhood ALL. METHODS: In 155 children with ALL, CSF samples were studied in parallel by CM and MFC. Patients were treated according to protocol ALL-MB-2008 for childhood ALL. The prognostic impact of the leukemia burden in CSF was determined categorizing the findings as positive/negative. In addition, the absolute blast cell count per 1 ml of CSF was studied as a continuous variable. RESULTS: CSF positivity was significantly more frequent using MFC compared with CM (35.3% vs. 15.3% of patients). The outcome of MFC-positive and MFC-negative patients was not different in clinically relevant patient risk groups-CNS1, standard and intermediate-risk groups. Using the quantitative approach, at the threshold level of 20 blasts per ml of CSF, patients could be divided into two groups with a significantly different outcome, irrespective of the clinical risk group, the type of CNS-directed therapy, and the CNS status determined by CM. CONCLUSIONS: Our data do not support the concept of re-stratification and modification of therapy based on qualitative CSF investigation by MFC. However, MFC is a highly sensitive technique of CSF investigation improving the definition of CNS involvement in childhood ALL, and quantitative measurement of blast cells in CSF, if well-organized, can be a useful additional tool for stratification of patients in clinical trials.
BACKGROUND: Usually, central nervous system (CNS) involvement in acute lymphoblastic leukemia (ALL) is diagnosed by cytomorphology (CM) of cerebrospinal fluid (CSF) on cytospin slides. Multicolor flow cytometry (MFC) provides the opportunity to detect low numbers of leukemia cells undetectable by CM. The present study aimed at evaluating the clinical significance of MFC for the diagnosis of CNS involvement at initial manifestation of childhood ALL. METHODS: In 155 children with ALL, CSF samples were studied in parallel by CM and MFC. Patients were treated according to protocol ALL-MB-2008 for childhood ALL. The prognostic impact of the leukemia burden in CSF was determined categorizing the findings as positive/negative. In addition, the absolute blast cell count per 1 ml of CSF was studied as a continuous variable. RESULTS: CSF positivity was significantly more frequent using MFC compared with CM (35.3% vs. 15.3% of patients). The outcome of MFC-positive and MFC-negative patients was not different in clinically relevant patient risk groups-CNS1, standard and intermediate-risk groups. Using the quantitative approach, at the threshold level of 20 blasts per ml of CSF, patients could be divided into two groups with a significantly different outcome, irrespective of the clinical risk group, the type of CNS-directed therapy, and the CNS status determined by CM. CONCLUSIONS: Our data do not support the concept of re-stratification and modification of therapy based on qualitative CSF investigation by MFC. However, MFC is a highly sensitive technique of CSF investigation improving the definition of CNS involvement in childhood ALL, and quantitative measurement of blast cells in CSF, if well-organized, can be a useful additional tool for stratification of patients in clinical trials.
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